title: Synthesis and biological evaluation of a diazepanone-based library of liposidomycins analogs as MraY inhibitors.
abstract: New inhibitors of the bacterial tranferase MraY are described. A scaffold strategy based on the diazepanone central core of liposidomycins, natural inhibitors of MraY has been developed. It involves the introduction of key structural fragments required for biological activity on enantiopure diazepanones by reductive amination, esterification and glycosylation. Biological evaluation of these compounds on MraY enzyme revealed interesting inhibitory activity for compounds displaying three fragments on the scaffold: a palmitoyl chain, an aminoribose part and an alkyluracil moiety. The inhibitors were also evaluated on MurG enzyme. The best compounds resulted in inhibition with IC50 values in the 100 μM range for one or the other enzyme.
authors.affiliation: Université Paris Descartes, UMR 8601 CNRS, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, 45 rue des Saints-Pères, 75006 Paris, France.
authors.forename: Janez
authors.initials: J
authors.lastname: Mravljak
authors.forename: Olivier
authors.initials: O
authors.lastname: Monasson
authors.forename: Bayan
authors.initials: B
authors.lastname: Al-Dabbagh
authors.forename: Muriel
authors.initials: M
authors.lastname: Crouvoisier
authors.forename: Ahmed
authors.initials: A
authors.lastname: Bouhss
authors.forename: Christine
authors.initials: C
authors.lastname: Gravier-Pelletier
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Merrer
mesh_terms: D000617:Aminoglycosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001381:Azepines / Q000737:chemistry*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014166:Transferases / Q000037:antagonists & inhibitors*; D017855:Transferases (Other Substituted Phosphate Groups)
chemical_list: D000617:Aminoglycosides; D001381:Azepines; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; C047544:liposidomycins; D014166:Transferases; D017855:Transferases (Other Substituted Phosphate Groups); C079803:mraY protein, Bacteria